Carfilzomib is a tetrapeptide epoxyketone, also known as (2S)—N—((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-yl-carbamoyl)-2-phenyl-ethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methyl-pentanamide, is represented by the following structure of Formula I:

Carfilzomib is marketed by Onyx Pharma under the trade name Kyprolis® is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.
U.S. Pat. No. 7,232,818 (“the '818 patent”) discloses a variety of peptide based compounds and their derivatives such as carfilzomib and its process for preparation thereof. The process disclosed in the '818 patent is schematically represented as follows:

The synthesis of carfilzomib as disclosed in the '818 patent has certain drawbacks as it involves:                a) coupling of N-boc-leucine of Formula II with phenyl alanine benzyl ester of Formula III in presence of excess quantity of coupling agents such as PyBOP of about 1.6 w/w mole equivalents and an additive of HOBt of about 1.6 w/w mole equivalents per mole of Formula III, in higher volume of solvent such as acetonitrile of about 45 v for the preparation of compound of Formula IV;        b) coupling of trifluoro acetic acid salt of Formula V with a compound of Formula VI in presence of excess quantity of coupling agents such as PyBOP of about 1.6 w/w mole equivalents and an additive of HOBt of about 1.6 w/w mole equivalents per mole of Formula IV, in higher volume of solvent such as acetonitrile of about 22 v for the preparation of compound of Formula VII;        c) coupling of trifluoro acetic acid salt of Formula XIII with morpholine acetic acid of Formula XII in presence of excess quantity of coupling agents such as PyBOP of about 1.6 w/w mole equivalents and an additive of HOBt of about 1.6 w/w mole equivalents per mole of Formula VII, in higher volume of solvent such as dimethylformamide of about 24 v for the preparation of compound of Formula XIV; and        d) coupling of Formula XV with a compound of Formula IX in presence of excess quantity of coupling agents such as PyBOP of about 1.6 w/w mole equivalents per mole of Formula XV, in higher volume of solvent such as acetonitrile of about 50 v for the preparation of carfilzomib;        
All the above mentioned amide coupling reactions involves use of excess quantity of coupling agent, excess quantity of an additive and solvent. Use of excess quantity of these reagents results to formation of higher quantity of unreacted HOBt, PyBOP and by product of tris(pyrrolidino phosphine) oxide thereby it necessitates separate purification techniques required for the high pure product, which contributes significant impact on the final yield and purity, thereby process not viable for large scale manufacturing. Further, the process involves long reaction times, which leads to an increase in the manufacturing cycle time and decrease in the product yield and quality.
Further, the '818 patent involves solvent extractions for isolation of intermediates and final product; which process also isolates unreacted coupling agents present in the reaction medium along with required intermediates and final product. Thereby additional purifications required to separate those unwanted coupling agents.
Journal of biological chemistry vol. 285, no. 51, pp. 40125-40134, 2010 discloses preparation of carfilzomib. The process disclosed in the article is schematically represented as follows:

U.S. Pat. No. 8,367,617 (“the '617 patent”) disclosed an alternate process for preparation of carfilzomib. The process disclosed in the '617 patent is schematically represented as follows:

However, '617 patent disclosed process also involves use of excess quantity of coupling agents same as mentioned for '818 patent.
PCT publication No. 2015/010436 (“the '436 publication”) discloses a process for preparation of carfilzomib. The process disclosed in the '436 publication is schematically represented as follows:

PCT publication No. 2015/032621 (“the '621 publication”) discloses a process for preparation of carfilzomib. The process disclosed in the '621 publication is schematically represented as follows:

PCT publication No. 2015/032622 (“the '622 publication”) discloses a process for preparation of carfilzomib. The process disclosed in the '622 publication is schematically represented as follows:

PCT publication No. 2015/121769 (“the '769 publication”) discloses a process for preparation of carfilzomib intermediate. The process disclosed in the '769 publication is schematically represented as follows:

PCT publication No. 2016/046843 (“the '843 publication”) discloses a process for preparation of carfilzomib. The process disclosed in the '843 publication is schematically represented as follows:

PCT publication No. 2016/069479 (“the '479 publication”) discloses a process for preparation of carfilzomib. The process disclosed in the '479 publication is schematically represented as follows:

Kyung et al., in Bioorganic & Medicinal Chemistry Letters 9 (1999) 2283-2288 discloses a process for the preparation of carfilzomib intermediate of Formula XVI starting from Weinrebamide of Formula XVII, which involves direct epoxidation of α,β-unsaturated ketone of Formula XVIII in presence of hydrogen peroxide to obtain diastereomeric mixture in compound of Formula XVI and Formula XVIa in a ratio of 1.7:1. However, this reference silent on isolation of intermediate compounds obtained from this process. The process disclosed by Kyung et al is schematically represented as follows:

PCT publication No. 2005/111009 (“the '009 publication”) discloses a process for preparation of carboxybenzyl (Cbz) protected compound of Formula XVI, by reduction of Cbz protected α,β-unsaturated ketone of Formula XVIII there by forming a diastereomeric mixture of allyl alcohol of Formula XIXa and Formula XIXb and epoxidation of allyl group of the obtained diastereomeric mixture of Formula XIX to obtain a diastereomeric mixture of compound of Formula XXa and Formula XXb, further oxidizing the hydroxy group of the obtained a diastereomeric mixture of Formula XX and the obtained compound was purified by flash chromatography to obtain diastereomeric mixture of compound of Formula XVI and Formula XVIa as a light yellow oil in a ratio of 9:1. The process disclosed in the '009 publication is schematically represented as follows:

PCT publication No. 2009/045497 (“the '497 publication”) discloses a process for stereoselective epoxidation of α,β-unsaturated ketone of Formula XVIII in presence of sodium hypochlorite or calcium hypochlorite to obtain diastereomeric mixture of compound of Formula XVI and Formula XVIa. The process disclosed in the '497 publication is schematically represented as follows:

Pereira et al., in ChemBioChem 2012, 13, 810-817 discloses a process for the preparation of compound of Formula XVI starting from boc-Leucine. The process disclosed by Pereira et al is schematically represented as follows:

Wang et al., in Chemistry—A European Journal 2012, vol. 18, Issue 22, Page-6750-6753 discloses a process for epoxidation of Formula XVIII in presence of hydrogen peroxide to obtain diastereomeric mixture of compound of Formula XVI and Formula XVIa in 1:7 ratio. The process disclosed by Wang et al is schematically represented as follows:

PCT publication No. 2014/003203 (“the '203 publication”) discloses a process for compound of Formula XVI, by reduction of compound of Formula XVIII in presence of amine borane complex and further converted in to diastereomeric mixture of compound of Formula XVI and Formula XVIa. The process disclosed in the '203 publication is schematically represented as follows:

As compound of Formula XVI and Formula XVIII have almost marginal polarity differences, compound of Formula XVI is readily isolated along with compound of Formula XVIII as an impurity in oily liquid state, thus compound of Formula XVIII is not possible to separate out from the mixture. Thereby unwanted formula XVIII is involved in the further sequential steps in preparation of carfilzomib, leads to formation of impurity of Formula 28.

All the above described processes involve isolation of intermediate compound of Formula XVIII, Formula XIX and Formula XVI as an oily nature, which are having higher content of process impurities thereby using such impure intermediates in the preparation of carfilzomib leads to formation of impure product.
Further, numerous CN publication No.(s) 103641890, 103864889, 103864898, 103936828, 103804469, 104086624, 104230857, 104356197, 104557793, 104672179, 104672180, 104710507, 105017181, 105273057, 105294501, 105218488 and 105440106 discloses process for preparation of carfilzomib and its intermediates thereof.
Reported literatures on preparation of carfilzomib involves N-boc-L-leucine of Formula II, L-phenyl alanine benzyl ester of Formula III, N-boc-L-Homophenylalanine of Formula VI and Formula IX as intermediates, which contains traces of its corresponding D-isomers or isoleucine compounds as impurities which tends to react in the same sequential manner to generate the corresponding isomers as impurities, which requires repetitive purifications to separate from the final API.
Different isomers of a chiral drug molecule bind differently to target receptors, one isomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects or sometimes even beneficial but entirely different effect, hence in the drug molecule the effective isomer is preferred in pure form, free of other undesired isomers, thus carfilzomib free of its other isomers would always be preferred.
Presence of impurities in a pharmaceutical compound is undesirable and health authorities in many jurisdictions (e.g. the Food and Drug Administration in the United States) have established guidelines relating to acceptable levels of impurities in pharmaceuticals. The need for and commercial utility of methods of reducing the level of impurities in any pharmaceutical are self-evident.
Based on the drawbacks mentioned above, there is a vital need to develop a process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof and its intermediates, which is readily amenable to large scale production with higher purity and yield.
Hence, present inventors focused research to simplify the process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof, which avoids mainly usage of excess quantity of reagents and solvents as compared to the prior-art processes, thereby making the process more suitable for commercial applications with higher purity, yield and obviate the problems associated with the reported process.
The present invention further relates to crystalline maleate salt of carfilzomib and its process for preparation thereof. The present invention furthermore relates to process for preparation of amorphous form of carfilzomib.
The present invention also relates to process for preparation of highly pure compound of Formula XVI and its intermediates in solid state, which is necessary for obtaining high pure carfilzomib API.